Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies

• Published in: Blood 2005-04, Vol.105 (8), p.3058-3065
• Main Authors: Orlowski, Robert Z., Voorhees, Peter M., Garcia, Reynaldo A., Hall, Melissa D., Kudrik, Fred J., Allred, Tammy, Johri, Anandhi R., Jones, Paul E., Ivanova, Anastasia, Van Deventer, Hendrik W., Gabriel, Don A., Shea, Thomas C., Mitchell, Beverly S., Adams, Julian, Esseltine, Dixie-Lee, Trehu, Elizabeth G., Green, Marie, Lehman, Mary Jo, Natoli, Susan, Collins, Jason M., Lindley, Celeste M., Dees, E.Claire
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - pharmacokinetics; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacokinetics; Bortezomib; Chemotherapy; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Doxorubicin - pharmacokinetics; Female; Hematologic Neoplasms - drug therapy; Humans; Liposomes; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Polyethylene Glycols; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - pharmacokinetics; Proteasome Inhibitors; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-07-2911

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.